Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C

Abstract

Background: National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat.

Methods: Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat.

Results: Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports.

Conclusions: Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Figure 1.

Patient flow diagram of National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (NCI-COG Pediatric MATCH) arm C. Patient flow diagram of NCI-COG Pediatric MATCH subprotocol C. Other reasons for ineligibility (n = 1 each) were lack of measurable disease, history of acute myelogenous leukemia, diagnosis of T-cell lymphoma, and prior treatment with tazemetostat.

Figure 2.

Diagnoses and genetic alterations of arm C. Tumor variants detected by gene and patient. The genes with the variants are indicated for each patient (each column represents a patient). Cooccurring mutations, histology, age, and treated patients as indicated. “Other tumor histologies”: 1 patient each: hepatocellular carcinoma, renal medullary carcinoma, ependymoma, and non-Langerhans cell histiocytosis (n = 1). PD = progressive disease; PR = partial response; SD = stable disease.

Figure 3.

Outcomes of patients treated on arm C. A) Swimmer’s plot for enrolled patients. B) Kaplan-Meier curve for progression-free survival. C) Kaplan-Meier curve for overall survival.

Figure 4.

Response of patient with non-Langerhans cell histiocytosis over 26 cycles of tazemetostat treatment. Black-outlined arrow denotes the lesion. Percent decrease was calculated by 2-dimensional measurements.